Significant improvement in early post-transplant survival rates has been achieved over the last decade for recipients of all types of allografts. Nevertheless, the need for further refinement of current immunosuppressive protocols is clearly emphasized by the morbidity and the annual attrition rate of at least 3-5% which are regularly observed in chronically immunosuppressed patients. The objective of this Program Project is to improve the outcome following organ transplantation by clarifying the mechanism involved in allograft rejection or tolerance. The ultimate objective is to develop immunosuppressive protocols which include a specific and long-lasting inhibition of only those elements of the immune response responsible for allograft rejection while other responses remain intact. The rational linking the objective of the 6 interrelated projects and 2 Core units is that since donor-specific non- reactivity can be detected in some allograft recipients, including man, it should be possible to identify and then reproducibly induce the immunologic perturbations which lead to this state. In large part, our efforts are directed to the use of monoclonal antibodies (mAbs), reactive with various cell surface antigenic determinants, both for immunologic monitoring of patients, receiving novel immunosuppressive agents, and for use in therapeutic regimens. The specific aims are to characterize, in a continum of models including mice selected for specific MHC incompatibilities, partially inbred swine, non-human primates, and ultimately man, the mechanisms of action of new immunosuppressive approaches and the state of reactivity or anergy that results from their application. The methodology of the studies includes genetic manipulation, renal or cardiac allografts in all animal models, flow cytometry and functional analyses of peripheral blood and graft infiltrating cells, and production and evaluation of new mAbs including bi-specific reagents. Studies exploring the effects of the immunosuppressive regimens on viral infection, the impact of viral infection on rejection or graft acceptance, and new anti-viral strategies are an essential element. Direct clinical application of the new therapeutic protocols developed is the central focus of the Program. Thus the benefits of these developments will be of immediate clinical relevance and hopefully will contribute to a reduction in the costs and morbidity associated with transplantation.